Phase II year
2017
(last award dollars: 2020)
Phase II Amount
$3,411,790
The goal of this project is to advance a new treatment, TLY012, as the first, disease modifying agent thataddresses two critical physiological and pathological features of chronic pancreatitis (CP) - fibrosis and severepain. CP is a progressive inflammatory disorder of the pancreas, predominantly caused by alcohol abuse. CPleads to pancreatic fibrosis and eventually irreversible destruction of the pancreas structure and function.Alcohol-related CP patients suffer from severe abdominal pain and increased risk of pancreatic cancer anddiabetes. However, there are no therapeutic agents that either address CP progression or eliminate recurrentpain associated with CP, resulting in a significantly underserved patient population. TLY012 is a long-acting,PEGylated recombinant human TRAIL that selectively eradicates activated pancreatic stellate cells (aPaSC),the key mediators of CP that induce fibrosis and pain, while leaving normal cells unharmed. In our preclinicalstudies, we found that systemically administered TLY012 to alcohol-induced CP rat models simultaneouslyameliorated pancreatic fibrosis and CP-associated pain as well as restored pancreatic function without causingany toxicity. The key objectives of the project involve the translation of TLY012 from the research stage tocompletion of an IND application to the FDA. In the first phase of the project (Phase I), manufacturing of TLY012for pre-clinical development, will include optimization and scale-up of the existing manufacturing process toproduce sufficient amount of TLY012 material. In addition, confirmatory pharmacology studies using the newlyproduced TLY012 in an alcohol-induced CP model and an initial toxicity assessment will be completed in rodentsand non-human primates in order to enable further safety testing in GLP toxicology studies. The effects of alcoholon the pharmacokinetics (PK) of TLY012 in vivo will also be investigated. Assay development for PK and anti-drug antibodies (ADA) testing will be done to support sample analysis from PK, pharmacology and toxicity aswell as formulation/stability studies. In the second phase of the project (Phase II), cGMP TLY012 will be producedusing the final production methods for additional testing in GLP toxicity and future use in Phase 1 clinical studies.This will include technical transfer of the scaled process to qualified manufacturing site; with subsequentmanufacturing of clinical material. Long term stability testing and clinical formulation development will also beinitiated. Once TLY012 is produced, the final IND enabling GLP toxicology studies (sub-chronic and chronic) inrodents and non-human primates will be completed, a clinical protocol will be created. At appropriate stages ofthis project, requests will be filed for early advisory meetings with FDA to seek advice on adjustments todevelopment strategy. As the final outcome of aforementioned studies an IND application will be filed to enablePhase 1 clinical studies in patients with alcohol-induced CP. Upon completion of project be successful, a highlyinnovative new drug, TL012 will be ready for entry into clinical trials.
Public Health Relevance Statement: Project Narrative
Chronic pancreatitis (CP) is one type of serious consequence from alcohol abuse and disease characterized
by progressive destruction of pancreas function that is accompanied by pancreatic fibrosis and constant and
severe abdominal pain. There are no curative therapeutic options, resulting in a significantly underserved CP
patient population. The goal of this project is to develop an innovative therapeutic agent that would stop or
reverse CP progress, thus consequently, diminish CP-associated pain and restore normal pancreatic function.
Project Terms: | | 